|Year : 2019 | Volume
| Issue : 1 | Page : 25-33
Efficacy of tamsulosin and tadalafil in relieving benign prostatic hyperplasia related symptoms: A randomized double blind placebo controlled cross-over study
Smita Pattanaik1, Harbhupinder Singh Sandhu2, Ravimohan Suryanarayan Mavuduru3, Shrawan Kumar Singh3, Arup Kumar Mandal3
1 Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Surgery, Government Medical College, Patiala, Punjab, India
3 Department of Urology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||24-May-2018|
|Date of Acceptance||19-Aug-2018|
|Date of Web Publication||02-Jan-2019|
Ravimohan Suryanarayan Mavuduru
Department of Urology, Postgraduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Tadalafil and Tamsulosin have both been approved for use in the management of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). This study compared the differential effects of these two on BPH-LUTS using a cross over study design.
Methods: Men ≥45 years of age, with an International Prostate Symptom Score (IPSS) ≥8 due to BPH-LUTS were included. The patients were randomized into sequence AB (tadalafil 10 mg OD followed by tamsulosin 0.4 mg OD) or BA in a double blind manner. All patients received a placebo lead-in period for 2 weeks, followed by an active drug for 6 weeks; placebo wash out for 4 weeks and then crossed over to second active drug for another 6 weeks. IPSS scores, Uroflowmetry parameters and International Index of Erectile Function-5 scores were recorded.
Results: Out of the 40 patients, 36 completed the study. Demographic and baseline characteristics were comparable between the two groups (AB and BA). No significant placebo effects were observed. Tadalafil and tamsulosin significantly improved the total IPSS score and quality of life (P < 0.05) as compared to the baseline. However, there were no significant differences between the two drugs with respect to extent of observed effect and which drug was prescribed 1st in the sequence respectively (P > 0.05). Significant period effect was observed (P < 0.05) i.e., the symptoms did not return to the baseline before the second treatment. Half of the nonresponders to either of the drugs responded when the drug was changed to the other. Tadalafil showed better improvement in EF score as compared to Tamsulosin.
Conclusion: Both Tadalafil and Tamsulosin improved LUTS and erectile function and those patients who did not respond to Tadalafil showed improvement with Tamsulosin and vice-a-versa.
|How to cite this article:|
Pattanaik S, Sandhu HS, Mavuduru RS, Singh SK, Mandal AK. Efficacy of tamsulosin and tadalafil in relieving benign prostatic hyperplasia related symptoms: A randomized double blind placebo controlled cross-over study. Indian J Urol 2019;35:25-33
|How to cite this URL:|
Pattanaik S, Sandhu HS, Mavuduru RS, Singh SK, Mandal AK. Efficacy of tamsulosin and tadalafil in relieving benign prostatic hyperplasia related symptoms: A randomized double blind placebo controlled cross-over study. Indian J Urol [serial online] 2019 [cited 2019 Apr 25];35:25-33. Available from: http://www.indianjurol.com/text.asp?2019/35/1/25/249241
| Introduction|| |
BPH and sexual dysfunction is often co-existent in ageing males. Population based and longitudinal studies have shown a strong correlation between erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) secondary to BPH. Sexual disorders and their related bother has been found to correlate strongly with age and the severity of LUTS, independent of the other co-morbidities., Although a causal link between LUTS and ED is not well established, four main pathophysiological mechanisms, with varying degrees of overlap currently support this relationship. Several studies have been conducted in men presenting with LUTS consistent with benign prostatic hyperplasia (BPH-LUTS) with and without concomitant ED to determine whether phosphodiesterase type 5 inhibitors (PDEIs) are effective for the treatment of symptomatic BPH.,,,,,,,,,,,,,,, They demonstrated that PDE-5 inhibitors are efficacious both alone and in combination with an alfa blocker in treating LUTS.,,,,, The current scientific evidence is insufficient to predict the differential response of either of the drugs and response of one of the agents when there is no response to the other for the treatment of LUTS. Hence, the best way to compare the efficacy would be a cross-over study design. Moreover, the sequence effect of these two agents has never been studied before. Thus the present study was designed to compare the efficacy of tamsulosin and tadalafil with regard to LUTS and ED in cases of BPH in a crossover design. The primary objective was to compare the magnitude of effect of Tamsulosin and Tadalafil in relieving BPH-LUTS using International Prostate Symptom Score (IPSS). Comparison of improvements in erectile function, assessments of residual effects on BPH-LUTS symptoms and safety of the two drugs were the secondary end points.
| Methods|| |
Men of 45 years of age or older with LUTS secondary to BPH with an IPSS >8 were screened. Those with prostate cancer, LUTS with neurological diseases, stricture urethra, urinary tract infections, episode of acute urinary retention within 4 weeks of initiation of the study, contraindications to the investigational drugs, and those unwilling to participate in the study were excluded. Patients with prior exposure of 5ARI or PDEI were also excluded. Those patients who satisfied the inclusion and exclusion criteria and provided a written informed consent were included in the study. A detailed medical history including history of present medication, general and systemic examination, basic laboratory investigations-hematology, renal function tests, urine analysis, Serum prostate-specific antigen values and urine culture were performed and recorded in the case record form. All patients entered into a 2 week of placebo (P2) lead-in period before randomization, irrespective of their previous alpha blocker intake or drug naive status.
Randomization and blinding
The patients were then randomized into one of the two sequences in a double blind manner (A-P4-B or B-P4-A), by using a computer generated random numbers. The two drug treatment interventions (A) Tadalafil 10 mg once daily (B) Tamsulosin 0.4 mg once daily were administered for a period of 6 weeks and with an intervening 4-week period of placebo (P4) wash out, then cross over to the second active drug for 6 weeks. The original appearance of the both the drugs and placebo were masked to look identical. They were packed in blister packs in a GMP (good manufacturing practices) certified facility. The allocation was concealed from the investigator who recruited the patients and assessed the outcomes. The execution of randomization, allocation concealment and dispensing of the medications were performed by another investigator who was not involved in the patient enrolment. The patients and the investigator who recruited them from the outpatient clinics were blinded to the treatment assignment [Figure 1]a.
|Figure 1: (a) Study flow and schema of randomization. (b) Consort diagram|
Click here to view
Assessments and follow-up
LUTS was assessed by IPSS and International Index of Erectile Function (IIEF-5) questionnaire. Voiding was assessed by Uroflowmetry and postvoid residual volume measurement. After baseline, the first follow-up visit was at the end of 2 weeks of placebo lead-in period. The second follow-up visit was at 8 weeks i. e. after the completion of first treatment period (either Tamsulosin or Tadalafil treatment taken for 6 weeks). The third follow-up visit was at 12 weeks i.e., at the end of the second placebo period or earlier if they find any difficulty or discomfort that warrants consultation. And the fourth follow-up was at 18 weeks. The points for follow-up were the 2nd last day or last day of the 6-week treatment period. The IPSS-total score, IPSS-voiding score, IPSS-storage score, IPSS-QOL score, PVR, corrected Q max and IIEF score were recorded at baseline and at all the follow-up visits. Patients were provided with 2 weeks of therapy along with compliance assessment sheet and were required to report at each follow-up visit. Further therapy was given at the follow-up till the next follow-up visit to ensure compliance. They were advised to preserve the emptied blister packs of the drugs and mark in the compliance assessment sheet for the days on which they had taken the drug. Compliance was assessed from the compliance assessment chart and the emptied blister packs of the drugs. A compliance rate of 80% or more was considered adequate. The patients were also enquired about any drug related side effects.
The sample size calculation was performed with a null hypothesis that there is no difference between tamsulosin (4 mg OD) and tadalafil (10 mg OD) for improving the IPSS-total in patients with BPH-LUTS in a randomized, double-blind, cross-over, non-inferiority study. So for a noninferiority margin of 3 point improvement in IPSS-total (as per the AUA 2010 guidelines), a standard deviation (SD) of difference between the treatments as 1.5, an alpha error of 0.5 and a beta error of 0.1 (power of the study 90%), the sample size for each cross-over phase was found to be 12. Assuming a 20% loss to follow-up the total sample size required for the cross-over study was 30. And we planned to recruit 40 patients in this study.
Data was expressed as mean + SD, scores (median and inter quartile range) or proportions as appropriate. Data sets were examined for their distribution pattern. The effect of treatment was assessed by applying repeated measures ANOVA and one way ANOVA. The effect of period, sequence and their interaction with treatment were also evaluated. Unpaired t-test and Chi-square test were applied as appropriate. A P < 0.05 was considered statistically significant.
| Results|| |
The study commenced after obtaining the ethics committee IRB approval. Ninety two patients were screened and 40 patients were included for the study. Twenty patients were allocated to each of the two treatment groups in a randomized double blind manner. A total of 36 patients completed the study [Figure 1]b.
The baseline parameters between the two groups were similar and there was no statistically significant difference between them [Table 1].
The analysis was first performed in the AB group (tadalafil followed by tamsulosin) and the BA group (tamsulosin followed by tadalafil) as a whole and then inter group. For simplistic representation, erectile function outcomes which was one of the secondary outcomes, is represented along with various IPSS parameters.
Effect of the treatment with respect to baseline in each of the treatment groups
In the AB group, the mean change during 2–8 weeks in IPSS-total score was -7.10, IPSS-voiding score was -5.36, IPSS-storage score was -1.73, IPSS-QOL score was -1.21, PVR was -13.00, corrected Qmax (cQmax) was + 0.06 and IIEF score was +2.72. There was significant change in IPSS-total score (P = 0.00), IPSS-voiding score (P = 0.00), IPSS-storage score (P = 0.00), IPSS QOL score (P = 0.00) and IIEF scores (P = 0.02) with Tadalafil. There was no significant change in PVR (P = 1.00) and cQmax (P = 1.00). The mean change during 12–18 weeks in IPSS-total score was -3.47, IPSS-voiding score was -2.63, IPSS-storage score was -0.84, IPSS-QOL score was -0.73, PVR was -36.15, cQmax + 0.03 and IIEF score was +2.20. There was significant change in IPSS-voiding score (P = 0.02) with Tamsulosin. There was no significant change in IPSS-total score (P = 0.06), IPSS-storage score (P = 0.60), IPSS-QOL score (P = 0.150), PVR (P = 1.00), cQmax (P = 1.00) and IIEF score (P = 0.19) with Tamsulosin [Table 2].
|Table 2: Effect of the Treatment with respect to baseline in each of the treatment groups|
Click here to view
In the group BA, the mean change during 2–8 weeks in IPSS-total score was -6.29, IPSS-voiding score was -4.58, IPSS-storage score was -1.70, IPSS-QOL score was -1.52, PVR was -41.23, cQmax was + 0.07 and IIEF score was +2.20. There was significant change in IPSS-total score (P = 0.00), IPSS-voiding score (P = 0.00), IPSS-QOL score (P = 0.00) and in IIEF-5 scores (P = 0.02) with Tamsulosin. There was no significant change in IPSS-storage (P = 0.10), PVR (1.00) and cQmax (P = 1.00) with Tamsulosin. The mean change during 12–18 weeks in IPSS-total score was -2.588, IPSS-voiding score was -1.47, IPSS-storage score was -1.11, IPSS-QOL score was -0.52, PVR was -21.94, cQmax was +0.05 and IIEF score was +4.13. There was no significant change in IPSS-total score (P = 0.23), IPSS-voiding score (P = 0.76), IPSS storage score (P = 0.16), IPSS-QOL score (P = 1.00), PVR (P = 1.00) and cQmax (P = 1.00) but a significant change was noted in IIEF score (P = 0.01) with Tadalafil [Table 2].
Overall drug effect
The mean difference in IPSS-total score, IPSS-voiding score, IPSS-storage score, IPSS-QOL score, PVR, cQmax and IIEF score between Tadalafil and Tamsulosin was 0.03, 0.19, 0.15, 0.26, 21.22, 0.04 and 1.55 respectively. The difference in IPSS-total score (P = 0.97), IPSS-voiding score (P = 0.84), IPSS-storage score (P = 0.77), IPSS-QOL score (P = 0.40), PVR (P = 0.37), cQmax (P = 0.47) and IIEF score (P = 0.17) between Tadalafil and Tamsulosin was statistically insignificant. To verify the results of ANOVA, the data was analyzed as per its distribution pattern. IPSS-total score, IPSS-voiding score, IPSS-storage score, IPSS-QOL score and cQmax were found to be normally distributed, PVR and IIEF were not. Unpaired t-test and Mann-Whitney U test were applied respectively [Table 3].
|Table 3: Treatment effect of Tadalafil and Tamsulosin considering both the periods|
Click here to view
In order to assess the residual effect of treatment, period effect and sequence effect were analyzed.
Period effect was assessed in two categories namely difference during the active drug treatment periods and difference during the two placebo periods.
Period effect of two active treatment periods (8 weeks and 18 weeks)
The mean difference in IPSS-total score, IPSS-voiding score, IPSS-storage score, IPSS-QOL score, PVR, cQmax and IIEF score between period 1 (A1+B1) and period 2 (B2+A2) was 3.66, 2.92, 0.74, 0.73, 1.93, 0.08 and 0.38. There was a statically significant difference in IPSS-total score (P = 0.00), IPSS-voiding score (P = 0.00) and IPSS-QOL score (P = 0.02) between period 1 and period 2 signifying a considerable period effect. There was no significant change in IPSS-storage score (P = 0.15), PVR (P = 0.93), cQmax (P = 0.20) and IIEF score (P = 0.73) between 2-8 weeks and 12-18 weeks. To verify the results of ANOVA, the data was analyzed as per its distribution pattern. IPSS-total score, IPSS-voiding score, IPSS-storage score, PVR and cQmax were found to be normally distributed whereas IPSS-QOL and IIEF were not. Unpaired t-test and Mann–Whitney U-test were applied respectively [Table 4].
|Table 4: Change in lower urinary tract symptoms parameters between period 1 and period 2|
Click here to view
Period effect between two placebo periods (2 weeks and 12 weeks)
A significant period effect was observed in both the groups with respect to IPSS-total, voiding and IPSS-QOL. In the AB group, there was a significant change in IPSS-total score (P = 0.00), IPSS-voiding score (P = 0.00), IPSS-QOL score (P = 0.00) and an insignificant change in IPSS-storage score (P = 0.09), PVR (P = 0.77), cQmax (P = 0.671) and IIEF score (P = 0.41) between 2 weeks and 12 weeks. Similarly in the BA group, there was a significant change in IPSS-total score (P = 0.02), IPSS-voiding score (P = 0.02), IPSS-QOL score (P = 0.00), IIEF score (P = 0.03) and an insignificant change in IPSS-storage score (P = 0.18), PVR (P = 0.09), cQmax (P = 0.84) between 2 weeks and 12 weeks [Table 5].
|Table 5: Change in lower urinary tract symptoms parameters between two baselines for the treatment groups (2 weeks and 12 weeks)|
Click here to view
Sequence effect of treatment
To see which sequence AB or BA was better, repeated measure ANOVA was applied between group AB and BA. The mean difference in scores IPSS-total (P = 0.77), IPPS-voiding (P = 0.55), IPSS-storage (P = 0.78), IPSS-QOL (P = 0.38), PVR (P = 0.45), cQmax (P = 0.71) and IIEF score (P = 0.81) were found to be insignificant, implying that there was no sequence effect [Table 6] and [Figure 2].
|Figure 2: Line diagram showing change in various assessment parameters in tadalafil and tamsulosin during the study|
Click here to view
Out of the forty patients randomized for the study, four patients dropped out. Three of these were found to be on Tamsulosin treatment, revealed at the end of the study period. One patient dropped-out because of worsening of LUTS, fatigability, myalgias and orthostatic hypotension, the second one was lost to follow up and the third one discontinued as he was diagnosed as a case of CLL and had febrile illness during the study. There was one patient whose LUTS worsened while on Tadalafil. Four patients on tadalafil and three patients on tamsulosin had Epigastric discomfort, which was relieved by proton pump inhibitors. Two patients had myalgia's, one had calf pain, one complained of decreased seminal volume and one patient developed herpes zoster during the study while on tadalafil. Adverse events were higher with Tadalafil but were self-limiting, easily manageable and did not lead to drop outs [Table 7].
Clinical response with Tadalafil and Tamsulosin (A1, B1, B2, A2)
Patients with >3 point improvement in their IPSS-total were considered responders, according to the AUA guidelines 2010 (minimally clinical important difference, change >3 score). In group AB, thirteen patients out of nineteen patients responded with Tadalafil (A1). When they were crossed over to Tamsulosin (B2), six continued to have >3 point improvement, seven patients failed to attain a 3 point improvement and three previous nonresponders (3/6; 50%) showed >3point response. In group BA, twelve patients out of seventeen patients responded with Tamsulosin (B1). When crossed over to Tadalafil (A2), three patients continued to have >3 point improvement, nine patients failed to attain the 3 point improvement and three previous nonresponders (3/5; 60%) became responders.
Clinical response in patients with prior erectile dysfunction with Tadalafil and Tamsulosin when given in period 1 and period 2 (A1, B2, B1, A2)
In group AB, there was a significant improvement in erectile function in period 1 (2–8 weeks) with Tadalafil and no significant change in period 2 (12–18 weeks) with Tamsulosin. Eleven patients (57.89%) out of nineteen patients had ED. Five patients (45.45%) out of eleven patients showed marked improvement in their IIEF score (change >3 score) in period 1 with Tadalafil (A1). Two new patients (18%) showed improvement with Tamsulosin (B2) in period 2. In group BA, there was a significant improvement in erectile function in period 1 (2–8 weeks) with Tamsulosin and also significant change in period 2 (12–18 weeks) with Tadalafil. Eleven (64.70%) out of seventeen patients had ED. Four (36.6%) out of eleven patients showed marked improvement in their IIEF scores (change >3score) in period 1 with Tamsulosin (B1). Four new patients (36.6%) showed improvement with Tadalafil (A2) in period 2.
| Discussion|| |
LUTS and ED, both impact the quality of life of an individual patient. Alfa blockers, which are the standard of care for BPH related urinary symptoms, have not shown consistent improvement in the erectile function, though there are some studies that report improvement.,, PDEI, which are the standard of care for ED, have been shown to cause a significant improvement in LUTS in patients with BPH in various studies, along with a remarkable effect on erectile function,,,,,,,,,,,,,,,, which has led to the US-FDA approval of tadalafil (2.5 and 5 mg) for treatment of LUTS consistent with BPH with or without ED.
Although both the classes of drugs have been shown to significantly improve LUTS when used as monotherapy and an additive effect has also been reported in a few studies,,,, there are many clinical questions which remain undefined. (1) which of the two drugs is better in a given patient? (2) how a patient, who has an initial reasonable response with one of the drugs, would respond to the other drug, which may be started if there is a gradual loss of therapeutic efficacy (3) whether a nonresponder with one of the drugs would show response with the other drug (4) Are there any specific patient clinical or uroflometric parameters that could guide the physician to choose one class of drug over the other.
This study was a pilot project with an aim to obtain the statistical data required for a larger study which can answer the above queries in our setting. We intended to evaluate the effect of both Tamsulosin 0.4 mg OD and tadalafil 10 mg OD on LUTS in the same patients prescribed as mono-therapies in separate periods of 6 weeks duration each, in a randomized double blind crossover manner. LUTS were evaluated by IPSS, uroflow parameters like Qmax and PVR were recorded and cQmax was calculated from Qmax. ED was assessed by a self administered IIEF-5 questionnaire. It appears from the analysis of the study results that there is no difference between tamsulosin 0.4 mg and tadalafil 10 mg with regard to the relief of LUTS. The clinical improvement in IPSS-total score with tadalafil and tamsulosin was seen in approximately 70% of the patients in our study. This is the clinical response criteria as per the AUA guidelines which suggests a >3 point decrease in total IPSS score from the baseline is indicative of a clinically meaningful improvement and this change is also consistent with that observed in other published tamsulosin and tadalafil studies.,,,,,,,
Our study provides some insight on how these two active medications behave over different time lines, and how much is the placebo effect. We did not find a significant placebo effect in the lead-in period or in the first washout period even though a few patients were already on alfa blockers at the entry into the study (4 in AB group and 4 in BA group). These findings were supported by the significant improvement in various IPSS and QOL scores after the first treatment period. However, the improvement on various IPPS parameters was seen primarily during the first treatment period and not so much during the second treatment period. This was evident because the scores at 12 weeks were significantly lower than that at 2 weeks [Table 4], both in the tadalafil first (AB) and tamsulosin first (BA) groups. Thus showing a significant period effect in some of the assessed parameters. This could be explained by the fact that the scores did not return to baseline at the beginning of the second treatment period, indicating that the 4 week placebo period was inadequate and a longer period (>4 weeks) is required. However, it could also be due to the continued effect of the drug even after complete washout. We did not perform a pharmacokinetic assessment of active drug which could have differentiated between the two. Such a period effect is commonly observed in a controlled setting like a clinical trial, where the urinary symptoms continue to improve on placebo despite discontinuation of the active treatment. Thus, if the duration of trial is long, subjective scores depict higher response rates as shown in the alfuzosin and tamsulosin cross-over trial by Karadağ et al. Since the IPSS and IIEF are subjective perception scores, they remained elevated even during the placebo washout period and did not return to baseline. However, there was no sequence effect, meaning that the magnitude of response is the same whether tamsulosin is given first or tadalafil is given first, implying the equi-effectiveness of both the drugs.
Another striking finding of our study is that nearly half of the nonresponders to either of the medications (tamsulosin or tadalafil) showed a clinical response when the drug was changed to the other. Thus the patients who do not respond to alfa blockers, PDEI may be helpful in alleviating the symptoms of LUTS and vice a versa. Patients also had a significant improvement in their erectile function which was better in the tadalafil first group, however even the tamsulosin first group showed a significant improvement in erectile function. This strengthens the theory of possible pathophysiological association between BPF-LUTS and ED. The observation that when tadalafil was crossed over to tamsulosin, there was a significant improvement in IPSS voiding, while when tamsulosin was changed over to tadalafil there was a significant improvement in IIEF score over the, hints about predominant effect of these two classes of drugs.
Limitations of the study
There are a few limitations of our study. We did not evaluate the prostate size of the patients during enrollment and we do not know how this variable might have influenced the efficacy of drugs in improving LUTS/BPH. However, there is no consensus regarding the association between the size of the prostate and severity of LUTS. Secondly, the sample size is small and these findings need to be confirmed in a large database for further recommendations. Third, as the LUTS parameters did not return to baseline during the 4 week placebo wash out period, the treatment effect in period 2 (12 weeks to 18 weeks) could not be specifically evaluated. Fourth, the men enrolled in the trial may represent a highly motivated sample, seeking medical advice for their LUTS and ED, which may not represent the true association of these two conditions overall.
We conclude that both Tadalafil and Tamsulosin significantly improve LUTS and erectile function. Half of patients who did not respond to Tadalafil may improve with Tamsulosin and vice-a-versa. Larger prospective randomized studies in Asian men with LUTS are required to identify the patient related parameters that may predict a better response with one drug over the other.
| References|| |
Rosen R, O'Leary M, Altwein J, Boyle P, Giuliano F, Kirby R, et al
. LUTS and male sexual dysfunction: the multi-national survey of the aging male (MSAM-7). European Urology Supplements. 2003 Feb 1; 2(1):94.
Bortz WM 2nd
, Wallace DH, Wiley D. Sexual function in 1,202 aging males: Differentiating aspects. J Gerontol A Biol Sci Med Sci 1999;54:M237-41.
McVary KT, McKenna KE. The relationship between erectile dysfunction and lower urinary tract symptoms: Epidemiological, clinical, and basic science evidence. Curr Urol Rep 2004;5:251-7.
McVary KT, Monnig W, Camps JL Jr., Young JM, Tseng LJ, van den Ende G, et al.
Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: A randomized, double-blind trial. J Urol 2007;177:1071-7.
Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: A dose finding study. J Urol 2008;180:1228-34.
Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E. A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol 2008;53:1236-44.
Oger S, Behr-Roussel D, Gorny D, Lecoz O, Lebret T, Denoux Y, et al.
Combination of doxazosin and sildenafil exerts an additive relaxing effect compared with each compound alone on human cavernosal and prostatic tissue. J Sex Med 2009;6:836-47.
Sairam K, Kulinskaya E, McNicholas TA, Boustead GB, Hanbury DC. Sildenafil influences lower urinary tract symptoms. BJU Int 2002;90:836-9.
Bechara A, Romano S, Casabé A, Haime S, Dedola P, Hernández C, et al.
Comparative efficacy assessment of tamsulosin vs. Tamsulosin plus tadalafil in the treatment of LUTS/BPH. Pilot study. J Sex Med 2008;5:2170-8.
McVary KT, Roehrborn CG, Kaminetsky JC, Auerbach SM, Wachs B, Young JM, et al.
Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 2007;177:1401-7.
Kaplan SA, Gonzalez RR, Te AE. Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. Eur Urol 2007;51:1717-23.
Liguori G, Trombetta C, De Giorgi G, Pomara G, Maio G, Vecchio D, et al.
Efficacy and safety of combined oral therapy with tadalafil and alfuzosin: An integrated approach to the management of patients with lower urinary tract symptoms and erectile dysfunction. Preliminary report. J Sex Med 2009;6:544-52.
Broderick GA, Brock GB, Roehrborn CG, Watts SD, Elion-Mboussa A, Viktrup L, et al.
Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. Urology 2010;75:1452-8.
Karadağ E, Öner S, Budak YU, Atahan Ö. Randomized crossover comparison of tamsulosin and alfuzosin in patients with urinary disturbances caused by benign prostatic hyperplasia. Int Urol Nephrol 2011;43:949-54.
Porst H, Kim ED, Casabé AR, Mirone V, Secrest RJ, Xu L, et al.
Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: Results of an international randomized, double-blind, placebo-controlled trial. Eur Urol 2011;60:1105-13.
Kim SC, Park JK, Kim SW, Lee SW, Ahn TY, Kim JJ, et al.
Tadalafil administered once daily for treatment of lower urinary tract symptoms in Korean men with benign prostatic hyperplasia: Results from a placebo-controlled pilot study using tamsulosin as an active control. Low Urin Tract Symptoms 2011;3:86-93.
Oelke M, Giuliano F, Mirone V, Xu L, Cox D, Viktrup L, et al.
Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol 2012;61:917-25.
Madani AH, Afsharimoghaddam A, Roushani A, Farzan A, Asadollahzade A, Shakiba M, et al.
Evaluation of tadalafil effect on lower urinary tract symptoms of benign prostatic hyperplasia in patients treated with standard medication. Int Braz J Urol 2012;38:33-9.
Jung JH, Jae SU, Kam SC, Hyun JS. Correlation between lower urinary tract symptoms (LUTS) and sexual function in benign prostatic hyperplasia: Impact of treatment of LUTS on sexual function. J Sex Med 2009;6:2299-304.
van Moorselaar RJ, Hartung R, Emberton M, Harving N, Matzkin H, Elhilali M, et al.
Alfuzosin 10 mg once daily improves sexual function in men with lower urinary tract symptoms and concomitant sexual dysfunction. BJU Int 2005;95:603-8.
Kumar R, Nehra A, Jacobson DJ, McGree ME, Gades NM, Lieber MM, et al.
Alpha-blocker use is associated with decreased risk of sexual dysfunction. Urology 2009;74:82-7.
Brock GB, McVary KT, Roehrborn CG, Watts S, Ni X, Viktrup L, et al.
Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: Integrated data analyses from 4 placebo controlled clinical studies. J Urol 2014;191:405-11.
Köhler TS, McVary KT. The relationship between erectile dysfunction and lower urinary tract symptoms and the role of phosphodiesterase type 5 inhibitors. Eur Urol 2009;55:38-48.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]